PROJECT SUMMARY Lung transplantation remains the only available treatment for many patients, who suffer from pulmonary failure. However, outcomes after lung transplantation continue to lag behind those after transplantation of other organs. Current immunosuppressive strategies for lung transplant patients are based on protocols that have been successfully used for recipients of other organs. However, such approaches do not take into account that immune responses to lung grafts differ from other commonly transplanted organs. Utilizing new mouse models of lung transplantation we have uncovered that tolerance to pulmonary grafts is regulated locally through interactions of immune cells within lymphoid aggregates that are newly formed in the graft. This application proposes to study mechanisms how tolerance is regulated after pulmonary transplantation and will allow for the development of new therapeutic strategies for lung transplant patients.